The overall objective of this proposal is to study the effect of renal failure on the hepatic metabolism of drugs. Specifically, the proposed investigations will aim at elucidating the mechanism responsible for the pronounced inhibition of the hepatic first-pass metabolism of propranolol as previously reported in chronic renal failure patients. The metabolic clearance of propranolol will be stuied in various uremic rat models. Appropriate experiments with the isolated perfused liver preparation will be performed to determine if the inhibition of propranolol metabolism in uremia is due to the accumulating endogeneous substances in uremic plasma (e.g., uremic toxins) or rather to a manifestation of pathological alteration in the microsomal drug metabolizing enzyme systems. Studies will also be carried out to determine if any of the propranolol metabolites can inhibit the metabolism of the parent drug.